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Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development
Ryosuke Tsunematsu1, Keiko Nakayama, Yuichi Oike
1Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Insights
Mammalian Fbw7 protein is essential for embryonic vascular development. Its deficiency impairs blood vessel formation by disrupting the Notch4-Hey1 signaling pathway, leading to embryonic lethality.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Mammalian Fbw7 is an F-box protein crucial for SCF ubiquitin ligase complexes.
- Fbw7 is expressed in embryonic endothelial cells, suggesting a role in vascular development.
Purpose of the Study:
- To investigate the role of Fbw7 in embryonic vascular development using a mouse knockout model.
- To elucidate the molecular mechanisms underlying Fbw7's function in angiogenesis.
Main Methods:
- Generation and analysis of Fbw7-deficient mice (Fbw7(-/-)).
- In utero embryonic lethality assessment and phenotypic analysis of vascular abnormalities.
- In vitro para-aortic splanchnopleural explant cultures.
- Analysis of Notch4 and Hey1 expression levels in Fbw7(-/-) embryos.
Main Results:
- Fbw7(-/-) embryos exhibited embryonic lethality between days 10.5-11.5 with severe vascular defects.
- Impaired vascular remodeling in the brain and yolk sac, and absence of major trunk veins were observed.
- Fbw7 deficiency led to accumulation of Notch4 and increased expression of its downstream target Hey1.
Conclusions:
- Mammalian Fbw7 is indispensable for embryonic vascular development.
- Fbw7 negatively regulates the Notch4-Hey1 pathway, which is critical for angiogenesis.
- Disruption of Fbw7 function leads to severe vascular abnormalities and embryonic lethality.
Abstract:
Mammalian Fbw7 (also known as Sel-10, hCdc4, or hAgo) is the F-box protein component of an SCF (Skp1-Cul1-F-box protein-Rbx1)-type ubiquitin ligase, and the mouse Fbw7 is expressed prominently in the endothelial cell lineage of embryos. We generated mice deficient in Fbw7 and found that the embryos died in utero at embryonic day 10.5-11.5, manifesting marked abnormalities in vascular development. Vascular remodeling was impaired in the brain and yolk sac, and the major trunk veins were not formed. In vitro para-aortic splanchnopleural explant cultures from Fbw7(-/-) embryos also manifested an impairment of vascular network formation. Notch4, which is the product of the proto-oncogene Int3 and an endothelial cell-specific mammalian isoform of Notch, accumulated in Fbw7(-/-) embryos, resulting in an increased expression of Hey1, which encodes a transcriptional repressor that acts downstream of Notch signaling and is implicated in vascular development. Expression of Notch1, -2, or -3 or of cyclin E was unaffected in Fbw7(-/-) embryos. Mammalian Fbw7 thus appears to play an indispensable role in negative regulation of the Notch4-Hey1 pathway and is required for vascular development.
